The GM2 gangliosidoses are a group of glycosphingolipid (GSL) lysosomal storage diseases which includes Tay-Sachs disease, Sandhoff disease and GM2 activator deficiency (Gravel et al (1995) in The Metabolic and Molecular Bases of Inherited Disease (Scriver et al) Vol 2, pp 2839-79, 3 vols, McGraw Hill, New York). They result from mutations in the genes encoding the hexosaminidase α subunit, β subunit and GM2 activator protein respectively. They are characterised by progressive neurodegeneration in response to high levels of lysosomal storage of GM2 and related GSLs, in neurones of the central nervous system (CNS) (Gravel et al (1995) supra). There are currently no therapies for these diseases. Potential therapeutic strategies for Tay-Sachs and Sandhoff disease include enzyme augmentation and substrate deprivation (Radin (1996) Glycoconj. J 13:153-7; Platt et al (1998) Biochemical Pharmacology 56:421-30).
Enzyme augmentation could be achieved clinically through strategies such as enzyme replacement, bone marrow transplantation, or gene therapy.
Defects in ganglioside biosynthesis are found in most human cancers and are thought to underlie the invasive and malignant properties of brain tumours (Hakomori (1996) Cancer Res. 56:5309-5318, Fredman et al. (1996) Glycoconj. J. 13:391-399).
Glycolipid metabolism also plays a critical role in other neuronal disorders, such as Alzheimer's disease and epilepsy. Niemann-Pick Type C patient neurons present with fibrillar tangles reminiscent of the morphology seen in Alzheimer's disease. Interestingly, GM1 ganglioside binding by amyloid beta-protein induces conformational changes that support its formation of fibrous polymers, and the fibrillar deposition of this protein is an early event in Alzheimer's disease (Yanagisawa et al (1995) Nat Med 1:1062-6, Choo-Smith et al (1997) Biol Chem 272:22987-90). Thus, decreasing GM1 synthesis could inhibit the fibre formation seen in Alzheimer's disease.
The imino sugar N-butyldeoxynojirimycin (NB-DNJ) is a potent inhibitor of alpha-glucosidase 1 (involved in N-glycan synthesis), and an even more potent inhibitor of glucosylceramide glucosyltransferase. NB-DNJ is currently undergoing clinical trials as a treatment for Gaucher and Fabry diseases, glycolipid storage disorders resulting from mutations in glucocerebrosidase and alpha-galactosidase A, respectively.